Heat shock proteins (Hsp's) play a key role in cell protection against various cell stress factors (i.e. toxic xenobiotic, chemotherapy, radiation) acting as a protective factor against the misfolding of essential proteins involved in maintaining cell functionality. Hsp90 proteins, members of these molecular chaperones are proteins that play a key role in the conformational maturation, stability and function of so-called “client” proteins, many of them belonging to the oncogenic protein family, such as Bcr-Abl, p53, Raf-1, Akt, ErbB2, EGFR, Hif and other proteins, as well as steroid hormone receptors. The inhibition of Hsp90 triggers the disruption of the Hsp90-client protein complex, and subsequently, its proteasome-mediated degradation causes loss of function and inhibition of cell growth. Interestingly, heat shock protein 90 has emerged as an important target in several diseases. In particular, the role played by Hsp90 in regulating and maintaining the transformed phenotype in cancers and neurodegenerative diseases has been recently identified, as well as its roles in fungal and viral infections (Solit D. B., et al., Drug Discov. Today, 2008, 13 (1-2), 38). In particular, Hsp90 inhibition has also been reported to be beneficial in the treatment of neurodegenerative diseases such as dementia with Lewy bodies, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, spinocerebellar ataxias, Parkinson, Huntington and Alzheimer's diseases (Taylor D. M., et al., Cell Stress Chaperones, 2007, 12, 2, 151; Yang Z., et al., Nat. Med., 2007, 13, 3, 348; Katsuno M., et al., Proc. Natl. Acad. Sci. USA, 2005, 102, 46, 16801; Gallo K. A., Chem. Biol., 2006, 13, 115; Luo W., et al., Proc. Natl. Acad. Sci., 2007, 104, 9511; Macario A. J., et al., N. Engl. J. Med., 2005, 353, 1489; Dou F., et al., Int. J. Mol. Sci., 2007, 8, 51); inflammatory diseases (Vega V. L., et al., Mol. Biol. Cell., 2003, 14, 764; Poulaki V., et al., Faseb J., 2007, 21, 2113); cerebral ischemia (Lu A., et al., J. Neurochem., 2002, 81, 2, 355) and malaria (Kumar R., et al., J. Biosci., 2007, 32, 3, 531).
Moreover, many Hsp90 client proteins are over-expressed in cancer, often in mutated forms, and are responsible for unrestricted cancer cell proliferation and survival. Interestingly, Hsp90 derived from tumour cells has particularly high ATPase activity with higher binding affinity to Hsp90 inhibitors than the latent form in normal cells, allowing specific targeting of Hsp90 inhibitors to tumour cells with little inhibition of Hsp90 function in normal cells (Chiosis G., et al., ACS Chem. Biol., 2006, 1, 5, 279). In addition, Hsp90 has also been recently identified as an important extracellular mediator for tumour invasion (Eustace B. K., et al., Nature Cell Biol., 2004, 6, 6, 507; Koga F., et al., Cell cycle, 2007, 6, 1393).
Thus, Hsp90 is considered a major therapeutic target for anticancer drug development because inhibition of a single target represents attack on all of the hallmark traits of cancer.
Since the discovery that two natural compounds, geldanamycin and radicicol, were able to inhibit Hsp90 function through binding to an ATP binding pocket in its N-terminal domain, the interest for Hsp90 inhibitors has grown. The natural antibiotic geldanamycin was shown to exhibit potent antitumour activity against human cancer cells (Whitesell L., et al., Cancer Res., 1992, 52, 1721), but significant toxicity prevented its clinical development (Supko J. G., et al., Cancer Chemother. Pharmacol., 1995, 36, 305).
The first-in-class Hsp90 inhibitor to enter clinical trials was the geldanamycin analogue 17-AAG (i.e., 17-allylaminogeldanamycin). Even though high in vitro activity characterizes this geldanamycin derivative, its interest is shadowed by poor solubility coupled to hepatotoxicity properties (Jez J. M., et al., Chem. Biol., 2003, 10, 4, 361). All clinical trials involving this compound have been halted in July 2010. Some of these above mentioned problems had been partially solved by the discovery of 17-dimethylaminoethylgeldanamycin, however all clinical development was halted because of unfavourable toxicity. Radicicol, a natural macrocyclic anti-fungal antibiotic, was found to inhibit Hsp90 protein by interacting at a different site of action than Geldanamycin (Sharma S. V., et al., Oncogene, 1998, 16, 2639). However, due to its intrinsic chemical instability it was deprived of in vivo activity.
Another important class of inhibitors resides in the purine scaffold. This class of derivatives was devised by structural homology with ATP. Among the many inhibitors developed within this family, PU24FC1 and BIIB021 were found to possess high in vitro and in vivo activity (He H., et al., J. Med. Chem., 2006, 49, 381; Lundgren K., et al., Mol. Cancer. Ther., 2009, 8, 4, 921).
High-throughput screening campaigns permitted the discovery of benzisoxazole derivatives endowed of Hsp90 inhibitory properties having a resorcinol moiety in position 3 (Gopalsamy A., et al., J. Med. Chem., 2008, 51,373).
Various other classes of Hsp90 inhibitors have been disclosed such as, 4,5-diarylpyrazoles (Cheung K. M., et al., Bioorg. Med. Chem. Lett., 2005, 15, 3338); 3-aryl, 4-carboxamide pyrazoles (Brough P. A., et al, Bioorg. Med. Chem. Lett., 2005, 15, 5197); 4,5-diarylisoxazoles (Brough P. A., et al., J. Med. Chem., 2008, 51, 196); 3,4-diaryl pyrazole resorcinol derivative (Dymock B. W., et al., J. Med. Chem., 2005, 48, 4212; Smith N. F., et al., Mol. Cancer. Ther., 2006, 5, 6, 1628); thieno[2,3-d]pyrimicline (WO2005034950, AACR 2009, Denver, Colo., poster 4684). Further heterocyclic derivatives containing three heteroatoms have also been described as possessing Hsp90 inhibitory properties. WO2009134110 disclosed 4,5-cliaryl thiadiazoles which demonstrated good Hsp90 binding affinity, but somehow rather modest cell growth inhibition. Another class of aza-heterocyclic adducts, namely triazole derivatives, has been disclosed abundantly. Indeed, within the triazole family of compounds, the 1,2,4-triazole scaffold has been profusely documented as possessing Hsp90 inhibiting properties. WO2009139916 (Synta Pharmaceuticals Corp.) disclosed tricyclic 1,2,4-triazole derivatives inhibiting Hsp90 at high micromolar concentrations. The same company later filed almost contemporaneously two further patent applications disclosing trisubstituted 1,2,4-triazole derivatives whose general formulae were partially overlapping and both covering a very large chemical space (WO10017479 and WO10017545). Within the first application the compounds are expected, to the say of the Applicant, to be endowed of numerous biological properties, but said expectation is not confirmed by any promising biological activity. Indeed, all reported biological data but one refer to a Hsp90 IC50 greater than 10 μM. Promising biological activity is however reported within WO10017545. Few days ago, Synta Pharmaceuticals Corp. Reported about an unique triazolone-containing Hsp90 inhibitor named ganetespib (previously referred as to STA-9090, or as its highly soluble phosphate prodrug STA-1474) potentially having broad application for a variety of human malignancies. This compound was claimed in WO06055760.

Interestingly, 1,2,3-triazole analogues have not been studied as much as the 1,2,4 regioisomers. A myriad of heterocyclic derivatives, among which 1,2,3-triazole compounds can be found, are encompassed within WO05000300 even though only three are specifically disclosed. U.S. Pat. No. 7,728,016 patent, based on the previous application, claims 1,2,3-triazole compounds, although only one of the three specifically disclosed 1,2,3-triazole was alleged to possess a Hsp90 IC50<10 μM. None of these derivatives are encompassed within the present application. However, meanwhile lots of Hsp90 inhibitors among the literature have demonstrated to possess nanomolar activity, no real teaching can be gathered from such patent since the biological data is expressed using a scale that does not allow one skilled in the art of heat shock protein to appreciate the true biological activity of this sole derivative. Therefore, example 3 of patent application U.S. Pat. No. 7,728,016 was synthesized and tested in house to assess its affinity toward the biological target and its cytotoxic property. Both were found to be rather modest being greater than 10 μM (i.e., binding affinity) and greater than 1 μM (i.e., cytotoxic activity). In the cytotoxic assay, 1 μM was the maximum concentration tested.
No Hsp90 inhibitor has yet made it through clinical trials and been approved by the Food and Drug Administration as a cancer treatment either for stability, toxicity or efficacy issues.
Therefore, the desire of potent and selective Hsp90 inhibitors remains an interesting and promising goal.
We have now found that 1,4,5-trisubstituted and 1,5-disubstituted 1,2,3-triazole derivatives are endowed of high and unexpected Hsp90 inhibitory properties. 1,2,3-triazole derivatives, structurally different (but with a certain degree of similarity) from the ones of the present invention, and possessing unrelated biological properties are known.
U.S. Pat. No. 7,803,822 patent discloses 1,2,3-triazole derivatives of formula 1 as thrombin receptor antagonists.

DE 10315570 discloses aryltriazoles of formula 2 as glycine transporter inhibitors.

Biaggi G., et al. reported lately 1,5-cliarylsubstituted 1,2,3-triazoles as potassium channel activators (Biaggi G., et al., Il Farmaco, 2004, 59, 5, 397). Glaxo Group Ltd. also reported mGluR5 receptor antagonists possessing the 1,2,3-triazole amide unit, as useful for treating psychotic disorders (WO2009115486).